Grant: Project Grant

A healthy immune system must swiftly react to non-self (e.g., microbes, cancer antigens) but must absolutely remain tolerant to self molecules. That is a question of life or death. T lymphocytes become tolerant to self during their education in the thymus. Notably, the thymus ages more rapidly than any other organ. Thymic involution begins at one year of age in humans and causes a progressive restriction in the diversity of the T-cell repertoire. Therefore, aged individuals are unduly susceptible to infections, cancer, autoimmune diseases, and they do not respond well to vaccines. From a global public health perspective, thymic involution arguably represents the most important immunopathology. It is therefore imperative that we understand precisely how the thymus functions in order to be able to enhance its output or to engineer thymic substitutes. In this context, it is a sobering thought that our understanding of the molecular definition of self and non-self is very rudimentary and that we do not understand the mechanisms of thymic involution. Accordingly, the two main objectives of this proposal are i) to uncover the molecular definition of the immune self and ii) to discover the mechanisms responsible for the precocious thymus ageing. To decipher the structure of molecules that define our immune self in the thymic medulla, we have developed a novel method that hinges on the integration of high-throughput genomic and proteomic data. Furthermore, our recent work suggests that thymic involution is due to the presence of excessive amounts of misbegotten proteins in thymic medullary cells. We will test novel experimental strategies in mice in order to determine whether disposal of these abnormal proteins could prevent thymic ageing. From a translational perspective, our studies should be relevant to the understanding, prevention and treatment of infections, cancer and autoimmune diseases.